4I1S: Melanoma Differentiation Associated Protein-5 Helicase Domain Complex With Inhibitor Non-structural Protein V

The retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) melanoma differentiation-associated protein 5 (MDA5) senses cytoplasmic viral RNA and activates antiviral innate immunity. To reveal how paramyxoviruses counteract this response, we determined the crystal structure of the MDA5 adenosine 5'-triphosphate (ATP)-hydrolysis domain in complex with the viral inhibitor V protein. The V protein unfolded the ATP-hydrolysis domain of MDA5 via a beta-hairpin motif and recognized a structural motif of MDA5 that is normally buried in the conserved helicase fold. This leads to disruption of the MDA5 ATP-hydrolysis site and prevention of RNA-bound MDA5 filament formation. The structure explains why V proteins inactivate MDA5, but not RIG-I, and mutating only two amino acids in RIG-I induces robust V protein binding. Our results suggest an inhibition mechanism of RLR signalosome formation by unfolding of receptor and inhibitor.
PDB ID: 4I1SDownload
MMDB ID: 107201
PDB Deposition Date: 2012/11/21
Updated in MMDB: 2017/07
Experimental Method:
x-ray diffraction
Resolution: 2.29  Å
Source Organism:
Simian virus 5 (strain W3)
Similar Structures:
Biological Unit for 4I1S: dimeric; determined by author and by software (PISA)
Molecular Components in 4I1S
Label Count Molecule
Proteins (2 molecules)
Melanoma Differentiation Associated Protein-5
Molecule annotation
Non-structural Protein V(Gene symbol: V/P)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB